Several agonists of insulin secretion have been shown to modulate, in a time dependent fashion, the insulin secretory response of pancreatic islets. In islets incubated with these agonists for a short period of time (15 minutes), insulin secretion in response to a subsequent glucose challenge is markedly enhanced, even after removal of the sensitizing agent. Both nutrient and non-nutrient agonists can induce this sensitization or memory. This response has been termed time-dependent,potentiation (TDP) and seems to be important for insulin secretion at physiologically relevant glucose concentrations. The mechanism mediating this response is unknown. Preliminary data are shown implicating PKC in this phenomenon. We propose to study in some detail the potential mechanisms of time-dependent potentiation. A project with four sections is outlined here. Using acetylcholine-induced and phorbol ester-induced time-dependent potentiation of insulin secretion as models, the mechanisms for sensitization will be studied. The activation of protein kinase C, the metabolism of diacylglycerol, the possible autoactivation of Calmodulin protein kinase II, and the production of 1,4,5-Inositol trisphosphate will be studied. The Principal Investigator is an endocrinologist with interest in the study of intracellular signalling and regulation, particularly in the control of insulin secretion. These interests are the main thrust of the sponsor's research effort. This fact, plus the richness and diversity of research at Yale will maximize the Principal Investigator's opportunities for growth as an academician.